Re-Evaluating Is the Complement Activation Product C3a A

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth This information is current as Liam G. Coulthard and Trent M. Woodruff of September 23, 2021. J Immunol 2015; 194:3542-3548; ; doi: 10.4049/jimmunol.1403068 http://www.jimmunol.org/content/194/8/3542 Downloaded from References This article cites 65 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/194/8/3542.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth Liam G. Coulthard and Trent M. Woodruff The complement activation product C3a is often de- which this agent was used (3). We wish to use this review to scribed as a proinflammatory mediator, alongside its draw much-needed attention to the potential anti-inflammatory downstream cousin, C5a. However, emerging studies rolesofC3a,soastorefocusthediscussiononitsrevisedpo- show that C3a has several anti-inflammatory facets in sition in the immune response, allowing new strategies for vivo. For example, in the acute inflammatory response, therapeutic targeting of C3a. Although the modern literature surrounding C3a and C5a C3a acts in direct opposition to C5a, through prevent- Downloaded from ing the accumulation of neutrophils in inflamed tissues frequently describe divergent functions for these peptides, their by independently regulating their mobilization. This discovery and characterization may explain why they are so acute, protective, and opposing activity of C3a to C5a often portrayed together as proinflammatory mediators. In the is also illustrated in models of septicemia. In this article, late 19th century, it was shown that Ag-exposed serum con- we reinvestigate the discovery and original classification tained both a heat-labile and a heat-stable bacteriocidal element. The heat-stable element was demonstrated to be Ab, of C3a as a proinflammatory mediator and highlight the http://www.jimmunol.org/ whereas the heat-labile element was termed “complement” by emerging studies demonstrating anti-inflammatory Paul Ehrlich, as it complemented the Ab response. The ana- effects for C3a in the immune response. It is our hope phylatoxins were discovered through incubation of serum that this review illuminates these apparently contradic- with Ag–Ab complexes, thus activating the classical pathway, tory roles for C3a and challenges the general dogma sur- and were named for their histamine-releasing ability (4). Al- rounding C3a, which, historically, has ubiquitously though unconfirmed at the time, the origin of the anaphyla- been described as a proinflammatory mediator. In light toxin activity was suspected to be complement, because of of this, we urge investigators to use “inflammatory mod- its heat-labile nature (5). This activity was finally ascribed to ulator” as the descriptor for C3a. The Journal of Im- complement split products with the identification of multiple by guest on September 23, 2021 munology, 2015, 194: 3542–3548. serum components of complement and the purification of C3a and C5a in the late 1960s. Initial experiments demonstrated that the release of the elusive anaphylatoxin was de- he complement cascade is a key component of the pendent on the presence of the initiating factors of the com- immune system and is essential in providing a bal- plement cascade and that the anaphylatoxin was released at, or anced response to injury and infection. Complement T shortly after, the involvement of C3 (6). With purification, can be activated through multiple initiating pathways, but all both C3a and C5a were shown to induce smooth muscle routes lead to the cleavage of the central complement com- contraction through release of histamine in a mutually re- ponents C3 and C5 to generate the small bioactive fragments dundant manner, both having similar “activity” at the guinea C3a and C5a (1). Both C3a and C5a are frequently and pig ileum (7). This led to the adoption of the term “com- consistently described in the literature as proinflammatory plement anaphylatoxin” for these peptides, although this label mediators, despite a limited number of reports of true pro- has recently been challenged (8) because it does not truly inflammatory activity for C3a in vivo. Furthermore, many encompass their widespread functions. reports, in fact, demonstrate an anti-inflammatory role for this major complement cleavage product in infection and disease. To add to the confusion, the only reported in vivo C3aR C3a generation, structure, and signaling antagonist (SB290157), which is used frequently in research Cleavage of C3 results in the formation of two split products: studies, was, in fact, demonstrated to act as a full agonist (2), C3a and C3b. C3a is generated at the convergence of all known thus clouding interpretations of results in disease models in complement-activation pathways, and its sibling at the point of School of Biomedical Sciences, University of Queensland, St. Lucia 4072, Queensland, Abbreviations used in this article: IR, ischemia-reperfusion; RAGE, receptor for ad- Australia vanced glycosylation end-products; Treg, regulatory T cell. ORCID: 0000-0003-1382-911X (T.M.W.). Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Received for publication December 9, 2014. Accepted for publication February 12, 2015. Address correspondence and reprint requests to Dr. Trent Woodruff, School of Bio- medical Sciences, University of Queensland, St. Lucia 4072, QLD, Australia. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403068 The Journal of Immunology 3543 cleavage, C3b, continues the propagation of the complement tor phosphorylation (23), are inhibited by the presence of C5a cascade (9). Classically, cleavage of C3 results from the action in human granulocytes (24). Studies in this area were perhaps of one of the C3 convertases, which are multiprotein com- the first reports of functional antagonism between C3a and plexes formed from the upstream cleavage events of comple- C5a at the molecular level. Until recently, C3a was thought to ment activation. Additionally, C3 can be cleaved by multiple be the only ligand for C3aR; however, the neuropeptide serine proteases present at sites of inflammation, most notably TLQP-21, a cleavage fragment of the VGL propeptide, was blood proteases, such as thrombin, and immune cell–derived shown to bind and activate murine C3aR through confor- proteases, such as cathepsin (10). mational change of the ligand upon receptor binding (25, 26). Structurally, C3a is a 77-aa peptide consisting of three to Additionally, the actions of C3a need not be mediated solely four helical regions and a series of nonregular residues at the through its canonical receptor, C3aR. In a model of experi- C-terminal responsible for binding at C3aR (11, 12). Short mental autoimmune encephalitis, ectopic CNS C3a expression +/+ portions of the C terminus were demonstrated to be necessary worsened disease outcome in C3ar1 animals. However, in both for agonist activity at C3aR and intrinsic antimicrobial mice lacking C3aR, the induced C3a expression improved activity (12, 13). The activity at C3aR of the terminal residues pathology, suggesting that the actions of C3a in CNS disease in isolation is far lower than that of the native molecule, and may not be confined solely to its interaction with C3aR (27). there is evidence that these flexible C-terminal residues are This finding was corroborated in a second paper from the stabilized in the conformation necessary to bind C3aR by the same group, demonstrating a protective effect for CNS C3a upstream a helix (14). Hence, this C-terminal region of C3a expression in LPS-induced endotoxic shock that was not di- Downloaded from minished in the absence of C3aR (28). has been a nidus for drug-design research, both in terms of C3a was also shown to bind to the receptor for advanced therapies capable of modulating C3aR activity and those that glycosylation end-products (RAGE) with a high affinity, but take advantage of the intrinsic antimicrobial abilities of the this interaction is more complex than a simple ligand–receptor molecule (15, 16). After its generation, C3a is cleaved quickly interaction (29, 30). Ruan et al. (29) demonstrated that C3a at the C-terminal arginine to form C3a-desArg. This molecule is able to form a complex with CpG oligonucleotides to en- http://www.jimmunol.org/ has no detectable activity at C3aR, but it was shown by some hance IFN-a release from mononuclear leukocytes. Intriguingly, groups to bind the second receptor

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